Novel Approaches for Oral Insulin Delivery - Pharmaceutical Technology

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Novel Approaches for Oral Insulin Delivery
The authors review various oral drug delivery systems that have been explored to increase patient compliance for insulin.

Pharmaceutical Technology
Volume 33, Issue 7

Clinical significance

Physiological insulin secreted by the pancreas enters portal circulation and inhibits hepatic glucose production. It undergoes metabolism in the liver to a significant extent (~50%). The ratio of plasma insulin in portal circulation versus that in peripheral circulation is two. The physiological hypoglycemic effect of insulin is a result of the absence of hepatic glucose production that is enhanced by an increase in glucose use caused by lower insulin levels in peripheral circulation. When insulin is injected subcutaneously, the plasma insulin concentration in portal and in peripheral circulation is almost equal. The hypoglycemic effect of insulin is a result of its action peripheral tissues. Oral delivery of insulin can mimic the physiological fate of insulin and may provide better glucose homeostasis. This type of delivery will also lessen incidences of peripheral hyperinsulinemia, which is linked to neuropathy and retinoendopathy (17).


Table I: Apparent permeability coefficient of insulin across various segments of gastrointestinal tract.*
In an attempt to prevent degradation of insulin in the stomach, Lowman et al. loaded insulin into poly(methacrylic-g-ethylene glycol) microspheres and administered them orally to healthy and diabetic Wistar rats (18). In the acidic pH of the stomach, insulin was protected from proteolytic degradation because the gels were unswollen as a result of the formation of intermolecular polymer complex. In the basic and neutral environment of intestines, the complexes dissociated, thereby leading to gel swelling and insulin release.

Copolymer networks of poly(methacrylic acid) grafted with poly(ethylene glycol) (PEG) exhibited reversible, pH-dependent swelling behavior as a result of the formation of interpolymer complexes between protonated pendant acid groups and the etheric groups on the graft chains (19). Gels containing equimolar amounts of metha acrylic acid/ethylene glycol (MAA/EG) exhibited the lowest degree of swelling at low pH as a result of increased complexation. The pH of the swelling solution affected the average network mesh size. The in vitro release of insulin from poly(MAA-g-EG) gels containing PEG grafts of MW 1000 Da indicated a significant release of insulin as the gel decomplexed. The results of in vitro studies have showed that insulin release rates could be controlled by appropriate adjustment of the structure of the gels.

Stimuli sensitive terpolymers of butyl methacrylate and acrylic acid (pH sensitive) of various MW with N-isoporopyl acrylamide/butylmethacrylate/acrylic acid feed mole ratio of 85/5/10 were used to modulate release of insulin from pH-sensitive polymeric beads. Protein drug loading from an aqueous medium into the beads was achieved by preparing a 7 or 10% (w/v) polymer solution with 0.2% (w/v) insulin at low pH and below the lower critical solution temperature (LCST) of the polymer (pH 2.0 and 4 C) and then dropping the solution into an oil bath above the LCST of the solution (35 C). This loading procedure maintained protein stability while achieving high loading efficiency (between 90 and 95%) in the beads. Insulinrelease studies from beads prepared from terpolymers of the same composition but increasing M W were performed at pH 2.0 and pH 7.4, at 37 C. There was negligible loss of insulin at pH 2.0 from the beads, indicating no burst effect. At pH 7.4, insulin release was seen from all the beads and the release rate was a function of the MW of the polymer (20, 21).

Reis et al. investigated alginate microparticles produced by emulsification-internal gelation as a promising carrier for insulin delivery (22). The alginate solution containing insulin protein was dispersed into a water immiscible phase. Gelation was triggered in situ by instantaneous release of ionic calcium from carbonate complex via gentle pH adjustment. Particle size could be controlled through the emulsification parameters, yielding spherical insulin-loaded microparticles. The recovery process was optimized, which improved yield, and ensured removal of residual oil from the particle surface. The optimum recovery strategy consisted in successive washing with a mixture of acetone-hexane-isopropanol coupled with centrifugation. This strategy led to small spherical particles with an encapsulation efficiency of 80% and a recovery yield of around 70%. In vitro release studies showed that alginate was not able to suppress insulin release in acidic media. However, this strategy preserved the secondary structure of insulin. Particles had a mean size lower than the critical diameter necessary to be orally absorbed through the intestinal mucosa followed by their passage to systemic circulation and thus can be considered as a promising technology for insulin delivery.


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